Checkpoint blockade with antibodies specific for the PD-1 and CTLA-4 inhibitory receptors can induce durable responses in a wide range of human cancers. However, the immunological mechanisms responsible for severe inflammatory side effects remain poorly understood. Here we report a comprehensive single-cell analysis of immune cell populations in colitis, a common and severe side effect of checkpoint blockade. We observed a striking accumulation of CD8 T cells with highly cytotoxic and proliferative states and no evidence of regulatory T cell depletion. T cell receptor (TCR) sequence analysis demonstrated that a substantial fraction of colitis-associated CD8 T cells originated from tissue-resident populations, explaining the frequently early onset of colitis symptoms following treatment initiation. Our analysis also identified cytokines, chemokines, and surface receptors that could serve as therapeutic targets for colitis and potentially other inflammatory side effects of checkpoint blockade.

使用针对 PD-1 和 CTLA-4 抑制性受体的特异性抗体进行检查点阻断可以在多种人类癌症中诱导持久反应。然而，导致严重炎症副作用的免疫机制仍然知之甚少。在这里，我们报告了结肠炎免疫细胞群的综合单细胞分析，这是检查点封锁的常见和严重副作用。我们观察到具有高度细胞毒性和增殖状态的 CD8 T 细胞的显着积累，并且没有调节性 T 细胞耗竭的证据。T 细胞受体 (TCR) 序列分析表明，很大一部分结肠炎相关 CD8 T 细胞来自组织驻留群体，这解释了治疗开始后结肠炎症状经常早发的原因。我们的分析还确定了细胞因子、趋化因子、